Impact of baseline CD4 cell count on CD4 cell count at 6 and 36 months
Figure 3 (upper panel) shows that patients with higher baseline CD4 cell count tended to have higher CD4 cell counts at 36 months, although there is substantial between-patient variability. Median CD4 cell counts at 36 months were 277 cells/μl (IQR 175–401) in patients with baseline CD4 cell count less than 25 cells/μl, rising to 789 cells/μl (590–1006) in patients with baseline CD4 cell count at least 500 cells/μl. In patients with CD4 cell count less than 200 cells/μl at baseline, 80 and 43% of patients achieved 36-month CD4 cell count greater than 200 and 500 cells/μl, respectively (lower panel of Fig. 3).
Impact of baseline HIV-1 RNA on HIV-1 RNA at 6 and 36 months
At 36 months, 78% of patients were virologically suppressed (HIV-1 RNA <500 copies/ml). Virological suppression at 36 months differed slightly according to the baseline HIV-1 RNA: the proportions with HIV-1 RNA less than 500 copies/ml were 72, 78 and 79% for baseline HIV-1 RNA less than 10 000, 10 000–100 000 and greater than 100 000 copies/ml, respectively (P < 0.001). Levels of HIV-1 RNA 6 months after cART initiation were, however, strongly associated with HIV-1 RNA at 36 months: only 54% of patients with HIV-1 RNA greater than 500 copies/ml at 6 months were virologically suppressed at 36 months, compared with 84% of patients who were virologically suppressed at 6 months (P < 0.001).
Impact of CD4 cell count at baseline, 6 and 36 months on rates of AIDS and death from 36 months
Table 2 shows associations of CD4 cell count and HIV-1 RNA at baseline, 6 and 36 months with rates of AIDS and death from 36 months after starting cART. The first and third columns show that, after adjusting for sex, transmission group, age and Centers for Disease Control and Prevention (CDC) stage at cART initiation, CD4 cell counts at each time point predicted rates of AIDS and of death from 36 months after cART initiation. There was a strong and graded association of CD4 cell count at 36 months with subsequent rates of AIDS and of death [hazard ratios 32.6 (95% CI 21.7–49.0) for AIDS and 26.4 (95% CI 17.3–40.2)] comparing participants with 36-month CD4 cell count less than 25 with those with at least 500 cells/μl. There were also graded associations of baseline and 6-month CD4 cell count with post-36-month rates of AIDS and of death, but the strength of associations declined as the time before 36 months increased.
Impact of HIV-1 RNA at baseline, at 6 and 12 months, on rates of AIDS and death from 36 months
There was a strong and graded association of the level of HIV-1 RNA at 36 months with subsequent rates of AIDS and of death, whereas 6-month HIV-1 RNA was also, though less strongly, prognostic. In contrast, baseline HIV-1 RNA was not prognostic for rates of AIDS or death from 36 months after cART initiation.
Impact of adjusting for CD4 cell count and HIV-1 RNA at other time points
The second and fourth columns of Table 2 show hazard ratios for the baseline, 6 and 36-month measurements of CD4 cell count and HIV-1 RNA, adjusting for both baseline characteristics and the measurements made at other time points. Thirty-six-month CD4 cell count and HIV-1 RNA were strongly associated with subsequent rates of AIDS and of death, although associations were attenuated after adjusting for each other and for previous measurements. In the mutually adjusted analyses, neither baseline CD4 cell count nor baseline HIV-1 RNA appeared prognostic for rates of AIDS or of death from 36 months after cART initiation (Table 2). There was a weak positive association of 6-month HIV-1 RNA with rates of AIDS, but the adjusted association of 6-month CD4 cell count was negative. This implies that, after accounting for 36-month measurements, greater increases in CD4 cell count between 6 and 36 months are associated with lower subsequent rates of AIDS.
In this large cohort collaboration, we showed that in patients who survive and are followed up for longer than 36 months there is a strong relationship between the CD4 cell count at cART initiation and the CD4 cell count at 6 and 36 months. Viral suppression at 36 months is associated with levels of HIV-1 RNA at 6 months, but only weakly associated with pretreatment levels. HIV-1 RNA at cART initiation is not prognostic for new AIDS events or death after 36 months. Associations of baseline CD4 cell count with rates of AIDS and death from 36 months are abolished once subsequent values are adjusted for. CD4 cell counts and HIV-1 RNA at 6 months after initial treatment response remain prognostic for new AIDS events but not the risk of death, after adjusting for 36-month values. CD4 cell count and HIV-1 RNA at 36 months were the strongest predictors of subsequent rates of AIDS and death.
Limitations and strengths
We excluded patients who had not been followed up beyond 36 months or who did not have measurements of CD4 cell count and HIV-1 RNA at 6 and 36 months, therefore the results presented here are only applicable to patients who survived for longer than 36 months after starting cART. Factors associated with exclusion – infection via IDU, male sex and lower viral load – have been linked to loss to follow-up and missing values in previous studies [27,28]. However, even though the exclusion of such patients will lead to less precise estimates of progression rates and associations, it is unlikely to bias estimates from the prognostic model since measured characteristics that differed between included and excluded patients were included in the models .
We were not able to assess the effects of some risk factors for death and new AIDS events, for example, adherence to antiretroviral treatment and concentration of haemoglobin, because they were either not collected or not collected in all the cohorts. However, adherence to antiretroviral treatment in naive patients is largely reflected by the success rate at 6 months and thereafter, which has been captured in our model. Haemoglobin concentration, which was not collected in all cohorts participating in ART-CC, has been shown to be prognostic for AIDS and death [2,29,30] but its omission from the models presented here is unlikely to change the qualitative conclusions about the relative importance of CD4 cell count and HIV-1 RNA at different times for prognosis from 36 months.
Strengths of our study include its large size and the broad range of patients included: from different industrialized countries with different settings of care and with wide variation in relevant clinical characteristics such as mode of transmission, age and extent of immune suppression before starting cART. Therefore, our results should be applicable to patients with HIV infection followed in clinical centres in industrialized countries who survived for longer than 36 months after starting cART. As for previous prognostic models from this collaboration , the presented models have high discriminatory power.
CD4 cell count
These analyses show that CD4 cell count remains a dominant prognostic factor among HIV-infected patients as time on cART increases. The impact of the CD4 cell count at cART initiation on the CD4 cell counts at 6 and at 36 months confirm the importance of initiating cART before CD4 cell counts decline too far [31,32]. Although CD4 cell counts continue to increase after 36 months in our data, and up to 5 years after cART initiation according to previous work  among patients who initiate cART at CD4 cell count less than 200 cells/μl and maintain virological suppression, only 25% of such patients have CD4 cell count greater than 500 cells/μl at 36 months. In patients who started cART at CD4 cell count less than 200 cells/μl, normalization of CD4 cell count is unlikely to be achieved . Coinfection by hepatitis viruses has been found to be associated with smaller CD4 cell count increases . Our models could not take into account infection by hepatitis viruses. However, they included history of IDU, which is a risk factor for coinfection, especially HCV, and CD4 cell count at 6 months, which could reflect the impact of coinfection on CD4 cell count increases.
When values at 6 and 36 months are taken into account, the CD4 cell count at baseline does not influence the prognosis for AIDS events or death, whereas CD4 cell count at 6 months is prognostic for AIDS but not for death. Whereas it appears that the impact of immunosuppression on death is totally captured by the last measurement of CD4 cell count, the impact of CD4 cell count at 6 months on prognosis for AIDS from 36 months requires careful explanation. The counterintuitive negative association of 6-month CD4 cell counts with rates of AIDS after 36 months is seen only after adjusting for the 36-month values. It implies that patients who reached a particular CD4 cell count at 36 months by increasing their CD4 cell count from 6 months and therefore by improving their immunological status have a better prognosis than patients who reached the same CD4 cell count by decreasing their CD4 cell count from 6 months. Therefore, after allowing for their 36-month CD4 cell count, patients with lower CD4 cell counts at 6 months (hence higher increases between 6 and 36 months) have better prognosis than patients with higher CD4 cell counts at 6 months (hence lower increases between 6 and 36 months). The patients for whom CD4 cell count decreased between 6 and 36 months after cART initiation could have interrupted their treatment, which is not assessed in our study, or received a less potent cART regimen, or have failed to adhere to treatment .
The association of HIV-1 RNA at 6 months with HIV-1 RNA at 36 months and AIDS after 36 months confirms the importance of early response to cART and the deleterious effect of virological failure after starting cART, which can be induced by lack of adherence to treatment and/or resistance . Therefore, the first 6 months under ART is a critical time in the care and follow-up of patients treated with cART [36,37]. In models adjusted for measurements at 0 and 36 months, virological suppression at 6 months remains prognostic for AIDS: this finding confirms the importance of achieving an early virological response. In the same way, patients with detectable HIV-1 RNA at 36 months have higher subsequent rates of AIDS or death, probably because of both their lower subsequent increases in CD4 cell count and higher rates of non-AIDS death associated with continuing HIV replication .
Although current values of CD4 cell count and HIV-1 RNA are the most important prognostic factors for subsequent rates of AIDS and death, consistent with our previous results , changes in CD4 cell count from 6 to 36 months and the value of 6-month HIV-1 RNA are also prognostic for subsequent rates of AIDS. Physicians should be aware of the prognostic importance of immunological status at cART initiation, which continues to influence subsequent CD4 cell counts, and of the initial virological response to cART, reflected by 6-month HIV-1 RNA.
We thank all patients, doctors, data managers, and study nurses who were involved in the participating cohort studies. ART Cohort Collaboration is supported by the UK Medical Research Council (MRC) grant G0700820. Sources of funding of individual cohorts include the Agence Nationale de Recherches sur le SIDA (ANRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the French, Italian and Swiss Ministries of Health, the Dutch Stichting HIV Monitoring, the European Commission, the British Columbia and Alberta Governments, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research and unrestricted grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen-Cilag, Pfizer and Roche.
Conflict of interest statement: M.M. has received travel grants from GlaxoSmithKline. A.M. has received reimbursement for either attending a symposium; a fee for speaking; or fees for consulting from various pharmaceutical companies from MS, Pfizer and Boehringer-Ingelheim. A.P. has received reimbursement for either attending a symposium; a fee for speaking; a fee for organizing education; funds for research; funds for a member of staff; or fees for consulting from various pharmaceutical companies including Roche, BMS, GSK, Abbott, Boehringer-Ingelheim, Gilead, Tibotec, and Oxxon Therapeutics. H.F. has participated in advisory boards of GSK, BMS, Gilead, MSD, Boehringer-Ingelheim; Janssen. The institution of H.F. has received unrestricted educational grants of Abbott, GSK, BMS, Roche, Gilead, MSD, Boehringer-Ingelheim, Pfizer, Essex, Janssen. T.S. has received a research grant from Pfizer. L.F. has received honoraria for advisory boards, a fee for speaking and a fee for organizing education from various pharmaceutical companies including Abbott, Bristol Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck and Janssen-Cilag. J.G. has served on advisory boards and or received research grants through University of Calgary from Abbott, Bristol Myers Squibb, Boehringer Ingelheim,Gilead Sciences,GlaxoSmithKline, Merck, Pfizer, Roche, and Tibotec. R.Ha has received travel grants from GlaxoSmithKline.
R.Ho has received travel grants and grant support from Abbott, Boehringer-Ingelheim, GlaxoSmithKline, and Merck. J.R. has received unrestricted grants from Essex, Roche, Abbott and Gilead. He has received consultancy fees, lecture fees, travelling expenses and payment of registration fees from Roche, Essex, Tibotec (Johnson & Johnson), Gilead, GlaxoSmithKline, Bristol-Myers Squibb, MSD, Boehringer-Ingelheim, Vertex and Abbott. M.S. has received grant or research support from, or acted as a consultant to Ardea Biosciences Avexa, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pain Therapeutics, Pfizer, Progenics, Tibotec, Tobira Therapeutics. JACS has received travel grants from GlaxoSmithKline and honoraria from Gilead Sciences. D.C. has received travel grants, consultancy fees, and honoraria from various pharmaceutical companies including Abbott, GlaxoSmithKline, Bristol-Myers-Squibb, Gilead, Roche, and Boehringer-Ingelheim. All other authors declare that they have no conflicts of interest.
Writing committee: Emilie Lanoy: INSERM, U943, Paris, F-75013 France; UPMC Univ Paris 06, UMR S943, Paris, F-75013 France. Margaret May: Department of Social Medicine, University of Bristol, Bristol BS8 2PR. Amanda Mocroft: Research Dept Infection and Population Health, University College London Medical School, Royal Free Campus, London, UK. Andrew Phillips: Research Dept Infection and Population Health, University College London Medical School, Royal Free Campus, London, UK. Amy Justice: Yale University School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA. Geneviève Chêne: INSERM, U897, Bordeaux, France; Université Victor Segalen Bordeaux 2, ISPED, France. Hansjakob Furrer: University Clinic for Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland. Timothy Sterling: Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. Antonella D'Arminio Monforte: Clinic of Infectious Diseases & Tropical Medicine, San Paolo Hospital, University of Milan, Italy. Lluís Force: Hospital de Mataró, Spain. John Gill: Division of Infectious Diseases, University of Calgary, Calgary, Canada. Ross Harris: Department of Social Medicine, University of Bristol, Bristol, BS8 2PR. Robert S. Hogg: British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University, Vancouver, Canada. Jürgen Rockstroh: Department of Internal Medicine, University of Bonn, Germany. Mike Saag: Division of Infectious Disease, Department of Medicine, University of Alabama, Birmingham, USA. Pavel Khaykin: Zentrum der Inneren Medizin, J.W. Goethe Universität, Frankfurt, Germany. Frank de Wolf: Academic Medical Centre, University of Amsterdam, the Netherlands. Jonathan A.C. Sterne: Department of Social Medicine, University of Bristol, Bristol BS8 2PR. Dominique Costagliola: INSERM, U943, Paris, F-75013 France; UPMC Univ Paris 06, UMR S943, Paris, F-75013 France; AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service de Maladies Infectieuses et Tropicales, Paris, F-75013 France.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
cART; CD4 cell count; mortality; plasma HIV-1 RNA; prognosis of AIDS